2-Aminomethyl-5-phenyloxazoles and the pharmaceutically acceptable acid addition salts thereof

ABSTRACT

2-Aminomethyl-5-phenyloxazoles and the pharmaceutically acceptable salts thereof have been found to be effective for meliorating inflammation in warm blooded animals.

BACKGROUND OF THE INVENTION FIELD OF THE INVENTION

This invention relates to 2-aminomethyl-5-phenyloxazoles and the pharmaceutically acceptable acid addition salt thereof which exhibit anti-inflammatory and analgesic activity.

SUMMARY OF THE INVENTION

This invention relates to compounds of the formula (I): ##STR1## wherein R₁ is phenyl or halophenyl; R' is (1) 4-(2-hydroxyethyl)-1-piperazinyl or (2) ##STR2## wherein R₂ and R₃ are selected from the group consisting of hydrogen and C₁ -C₁₀ alkyl. Also encompassed within this invention are pharmaceutically acceptable salts thereof. This invention also relates to a method of meliorating inflammation in warm blooded animals, particularly mammals, which comprises administering to said animal an anti-inflammatory effective amount of a compound of formula (I).

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

This invention relates to a group of 2-aminomethyl-5-phenyloxazoles of the formula (I): ##STR3## wherein R₁ is phenyl or halophenyl such as 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 4-iodophenyl and the like: R' is (1) 4-(2-hydroxyethyl)-1-piperazinyl or (2) ##STR4## wherein R₂ and R₃ are selected from the group consisting of hydrogen and alkyl of 1-10 (preferably 1-6) carbon atoms, such as methyul, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, isopentyl, hexyl, oxtyl, decyl and the like. Suitable R₁ groups in the above formula (I) are phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 4-fluorophenyl, 4-bromophenyl and the like.

Suitable methyl, octyl, ##STR5## groups in the above formula (I) are amino, methylamino, ethylamino, propylamino, isopropylamino, butylamino, sec-butylamino, isubutylamino, dimethylamino, diethylamino and the like.

ILLUSTRATIVE OF THE COMPOUNDS OF THIS INVENTION ARE THE FOLLOWING:

2-dimethylaminomethyl-5-(4-chlorophenyl) oxazole

2-methylaminomethyl-5-(4-chlorophenyl) oxazole

2-aminomethyl-5-(4-chlorophenyl) oxazole

2-aminomethyl-5-(4-fluorophenyl) oxazole

2-methylaminomethyl-5-phenyloxazole

2-dimethylaminomethyl-5-phenyloxazole

2-aminomethyl-5-phenyloxazole

2-ethylaminomethyl-5-phenyloxazole

2-propylaminomethyl-5-phenyloxazole

2-isopropylaminomethyl-5-phenyloxazole

2-butylaminomethyl-5-phenyloxazole

2-ethylaminomethyl-5-(4-chlorophenyl) oxazole

2-isopropylaminomethyl-5-(4-chlorophenyl) oxazole

2-methylaminomethyl-5-(4-fluoropuenyl) oxazole

2-ethylaminomethyl-5-(4-fluorophenyl) oxazole

2-aminomethyl-5-(2-chlorophenyl) oxazole

2-methylaminomethyl-5-(3-chlorophenyl) oxazole

2-methylaminomethyl-5-(2-chlorophenyl) oxazole

2-ethylaminomethyl-5-(2-chlorophenyl) oxazole

2-ethylaminomethyl-5-(4-bromophenyl) oxazole

2-ethylaminomethyl-5-(3,4-dichlorophenyl) oxazole

2-propylaminomethyl-5-(4-chlorophenyl) oxazole

2-propylaminomethyl-5-(3-chlorophenyl) oxazole

2-propylaminomethyl-5-(4-fluorophenyl) oxazole

2-diethylaminomethyl-5-(4-chlorophenyl) oxazole

2-[4-(2-hydroxyethyl)-1-piperazinylmethyl]-5-(4-chlorophenyl) oxazole

2-[4-(2-hydroxyethyl)-1-piperazinylmethyl]-5-(3-chlorophenyl) oxazole

2-[4-(2-hydroxyethyl)-1-piperazinylmethyl]-5-(2-chlorophenyl) oxazole

2-[4-(2-hydroxyethyl)-1-piperazinylmethyl]-5-(4-fluorophenyl) oxazole

2-[4-(2-hydroxyethyl)-1-piperazinylmethyl]-5-(4-bromophenyl) oxazole

2-[4-(2-hydroxyethyl)-1-piperazinylmethyl]-5-(3,4-dichlorophenyl) oxazole

The pharmaceutically acceptable acid addition salts of the above compounds are, of course, also included within the scope of this invention.

It will be understood that the term "pharmaceutically acceptable acid addition salts" as used herein is intended to include non-toxic salts of the compounds of this invention with an anion.

Representative of such salts are hydrochlorides, hydrobromides, sulfates, phosphates, nitrates, acetates, succinates, adipates, propionates, tartrates, maleates, citrates, benzoates, toluenesulfonates, and methanesulfonates. Of the compounds of this invention, it will be understood that the following compounds are most preferred due to their high level of anti-inflammatory and analgesic activity.

2-methylaminomethyl-5-phenyloxazole 2-ethylaminomethyl-5-(4-chlorophenyl) oxazole

2-[4-(2-hydroxyethyl)-1-piperazinylmethyl]-5-(4-chlorophenyl) oxazole

The above compounds are intended only to illustrate the variety of structures which can be used in the process of this invention, and the above listing is not to be construed as limiting the scope of the invention.

For the preparation of the compounds of this invention, various methods can be employed depending upon the particular starting materials and/or intermediates involved.

The 2-aminomethyl-5-phenyloxazole can be prepared by the condensation of a 2-halomethyl-5-phenyloxazole with at least an equimolar amount of a corresponding primary or secondary amine.

The following reaction equation illustrates this method of preparation. ##STR6## In the above formulas, R₁ and R' are as defined herein above and when R' is ##STR7## at least one of R₂ and R₃ is alkyl, and X is halogen.

The condensation reaction is generally effected in a suitable reaction-inert solvent in the presence of a base, such as an organic base (triethylamine, pyridine) or a solution of an inorganic base (sodium hydroxide, sodium carbonate) for a period of from 1 to 30 hours.

The preferred solvents for the condensation includes water, methanol, ethanol, dimethylformamide, tetrahydrofuran and the like. The reaction temperature is not critical, and generally ranges from 0° to 200° C, preferably from 15° to 100° C.

The amount of the primary or secondary amine (III) to be used is generally in the range of 1 to 10 moles per mole of the 2-halomethyl-5-phenyloxazole (II), with from 1 to 3 moles per mole of the 2-halomethyl-5-phenyloxazole (II) being preferred.

After the reaction is complete, the reaction mixture is concentrated to remove the solvent and the excess amine. The residue is partitioned between NaOH solution and chloroform, the chloroform layer separated and dried over a suitable drying agent, and then the solvent is evaporated under reduced pressure. The resulting product (I), after having been converted to the acid addition salt by interaction of the product with an acid in an appropriate medium, e.g., methanol or ethanol, can be recrystallized from a suitable solvent, e.g., methanol or ethanol.

2-Aminomethyl-5-phenyloxazoles wherein R₂ and R₃ are hydrogen, can be prepared by the reaction of a 2-halomethyl-5-phenyloxazole with potassium phthalimide followed by decomposition of the obtained N-(5-phenyl-2-oxazolyl) methylphthalimide with hydrazine hydrate.

The following reaction equation illustrates this method of preparation. ##STR8## In the above formulas, X is halogen. The reaction between the 2-halomethyl-5-phenyl oxazole (II) and potassium phthalimide (IV) is generally effected in a suitable reaction-inert solvent at a temperature of from 15° to 100° C for a period of from 1 to 30 hours.

The preferred solvents are dimethylformamide and ethanol. The amount of potassium phthalimide to be used is generally in the range of 1 to 10 moles per mole of the 2-halomethyl-5-phenyloxazole (II), with from 1 to 2 moles per mole of the 2-halomethyl-5-phenyloxazole (II) being preferred.

Upon completion of the reaction, the reaction mixture is poured into water to give the precipitate (V) which is filtered and can be purified by recrystallization from a suitable solvent, e.g., ethanol.

The decomposition of the N-(5-phenyl-2-oxazolyl)methylphthalimide (V) by the action of hydrazine hydrate is generally effected in an alcohol at a temperature of from 15° to 100° C for a period of from 1 to 10 hours.

In general, hydrazine hydrate is used in an amount of 1 to 3 moles per mole of the N-(5-phenyl-2-oxazolyl) methylphthalimide (V).

After the reaction is complete, the formed precipitate is filtered off. The filtrate is evaporated to dryness, and the residue, after having been converted to the acid addition salt, can be purified by recrystallization from a suitable solvent, e.g., ethanol.

The 2-halomethyl-5-phenyloxazoles (II) starting materials can be prepared by the condensation of a phenacylamine with a haloacetyl halide followed by cyclization of the obtained N-phenacylhaloacetamide.

The following reaction equation illustrates this method of preparation. ##STR9## In the above formulas, R₁ and X are as defined herein above. The condensation of the phenacylamine (VII) with the haloacetyl halide (VII) is carried out in a suitable solvent, e.g., benzene-water, in the presence of a base, such as sodium hydroxide at a temperature of 0° to 50° C for a period of 1 to 5 hours.

A convenient method of isolation comprises extraction of the product with a water immiscible solvent, e.g., benzene, followed by removal of the solvent. The resultant product can be used in this crude state for the subsequent reaction or can be recrystallized from an appropriate solvent, e.g., ethanol.

The cyclization of the N-phenacylhaloacetamide (IX) to the 2-halomethyl-5-phenyloxazole (II) is carried out in a suitable solvent, e.g., benzene or toluene, in the presence of a dehydrating agent, e.g., phosphorous oxychloride, or sulfuric acid at a temperature of 15° to 100° C for a period of 1 to 5 hours.

The product is conveniently isolated by pouring the reaction mixture into water followed by extraction with a water immiscible solvent such as chloroform. The organic layer is dried over a suitable drying agent and concentrated in vacuo. The isolated product can be used in this crude state or may be further purified by recrystallization.

The 2-aminomethyl-5-phenyloxazoles of this invention form acid addition salts with any of a variety of inorganic and organic acids.

The product of the reactions described above can be isolated in the free form or in the form of an acid addition salt. In addition, the product can be obtained as pharmaceutically acceptable acid addition salts by reacting one of the free bases with an acid.

Likewise, treatment of the salts with a base results in a regeneration of the free base.

Pharmacological testing of the 2-aminomethyl-5-phenyloxazoles has demonstrated that they are useful as anti-inflammatory agents. Analgesic activity has also been found in the compounds of this invention.

The anti-inflammatory activity of the compounds of the present invention was demonstrated in the following test:

The anti-inflammatory activity of the 2-aminomethyl-5-phenyloxazoles was compared with that of aminopyrine.

Eight male rats of Wistar-King strain, each weighing between 120 to 150 grams, were used for each group. The hind paw of the rats was injected subcutaneously with 0.1 ml of 1% carrageenin suspension. The volume of the paw was measured plethysmographically 3 hours after the injection, and the difference in volume between the edematous foot and the normal foot was regarded as the degree of edema. Each percent inhibition was calculated in comparison with the control. The test compounds were administered orally 30 minutes before the injection of carrageenin.

The analgesic activity of the 2-aminomethyl-5-phenyloxazoles was compared with that of aminopyrine.

(A) Writhing syndrome induced by acetic acid

Six male mice of ddY strain, each weighing between 25 to 30 grams were used in the present experiment. The animals were injected intraperitoneally with 0.1 m/10 g of a 0.6% aqueous acetic acid solution 10 minutes after the test compound was injected subcutaneously. Thereafter, the total number of writhings of a group was recorded for 20 minutes, and percent inhibition was calculated in comparison with the control. ED₅₀ was calculated according to Litchfield-Wilcoxon's method.

(B) Electrical stimulation method

Five male mice of ddY strain, each weighing between 25 to 30 grams were used for each group. Bipolar electrode was placed on the tail root of mouse. The mouse was stimulated with the square wave (5 m sec, 1 Hz), and the minimum voltage of squeak response was measured at 5, 10, 15, 30, 45 and 60 minutes after intraperitoneal administration of the test compound. Positive analgesic response was determined in cases where increase in the minimum voltage was observed. ED₅₀ was calculated according to Weil's method. The actute toxicity values (LD₅₀) of the 2-aminoethyl-5-phenyloxazoles were determined in the following manner:

The animals were administered intraperitoneally with the test compounds, and mortality was observed for 168 hours. LD₅₀ was calculated according to Weil's method. The results are shown in Table I.

                                      TABLE I                                      __________________________________________________________________________                                     Anti-inflammatory                                                              Activity                                                                       (carageenin-                                                                   induced rat paw                                                                inflammation)                                                                           Analgesic Activity                                                             AcOH induced                                                              Percent                                                                             Writhing in                                                                            Electrical                                                    Oral                                                                               Inhibition                                                                          Mice    Stimulation                                                   Dose                                                                               of   ED.sub.50                                                                              ED.sub.50                                                                             LD.sub.50 in                                                                   Mice                   Compound                        mg/kg                                                                              Swelling                                                                            (mg/kg. s.c.)                                                                          (mg/kg.                                                                               (mg/kg.                __________________________________________________________________________                                                             i.p.)                   ##STR10##                      25 50 100                                                                           5 40 48                                                                            10.1    32     238                     ##STR11##                      12.5 25 50 100                                                                     16 43 65 60                                                                         1.9     35     283                     ##STR12##                      100 7    78      77     336                     ##STR13##                      25 50  100                                                                          5 40 48                                                                            10.1    32     238                     ##STR14##                      12.5 25 50 100                                                                     16 43 65 60                                                                         1.9     35     283                     ##STR15##                      100 7    78      77     336                     ##STR16##                      100 17   22      46     141                     ##STR17##                      25 50 100                                                                          25 29 65                                                                            6       50     476                     ##STR18##                       50 100                                                                            23 47        21.4   141                     ##STR19##                       50 100                                                                            38 55               141                     ##STR20##                      25 50 100                                                                          28 58 42            283                     ##STR21##                      100 21                  283                     ##STR22##                      100 14                  141                     ##STR23##                      100 14           54     141                     ##STR24##                      100 22                  168                     ##STR25##                      25 50 100                                                                          27 56 68            141                     ##STR26##                       50 100                                                                            24 38        47     566                     ##STR27##                       50 100                                                                             4 32               283                     ##STR28##                       50 100                                                                            45 53        54     238                     ##STR29##                       50 100                                                                            24 44               238                     ##STR30##                      100 14                  141                     ##STR31##                      100 6                   283                     ##STR32##                       50 100                                                                             8 54               336                     ##STR33##                      12.5 25 50 100                                                                      6 27 57 50                                                                         16.0    30.8   283                    Aminopyrine                     12.5                                                                               9    37      96     270                                                    25  23                                                                         50  47                                                                         100 65                                         __________________________________________________________________________

The therapeutic agents of this invention may be administered alone or in combination with pharmaceutically acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmaceutical practice. For example, the compounds may be injected parenterally, that is, intramuscularly, intravenously or subcutaneously. For parenteral administration, the compounds may be used in the form of sterile solutions containing other solutes, for example, sufficient saline or glucose to make the solution isotonic. The compounds may be administered orally in the form of tablets, capsules, or granules containing suitable excipients such as starch, lactose, white sugar and the like. The compounds may be administered sublingually in the form of troches or lozenges in which each active ingredient is mixed with sugar or corn syrups, flavoring agents and dyes, and then dehydrated sufficiently to make the mixture suitable for pressing into solid form. The compounds may be administered orally in the form of solutions which may contain coloring and flavoring agents.

Physicians will determine the dosage of the present therapeutic agents which will be most suitable, and dosages vary with the mode of administration and the particular compound chosen. In addition, the dosage will vary with the particular patient under treatment.

When the composition is administered orally, a larger quantity of the active agent will be required to produce the same effect as caused with a smaller quantity given parenterally. The therapeutic dosage is generally 10-50 mg/kg of active ingredient parenterally, 50-300 mg/kg orally per day.

Having generally described the invention, a more complete understanding can be obtained by reference to certain specific examples, which are included for purposes of illustration only and are not intended to be limiting unless otherwise specified.

EXAMPLE 1 (A) N-(4-chlorophenacyl) chloroacetamide

To a well stirred suspension of 20.6 g of 4-chlorophenacylamine hydrochloride in 70 ml of benzene and 70 ml of water which was cooled to below 7° C were added simultaneously 110 ml of 2N NaOH solution and 12.4 g of chloroacetyl chloride dissolved in 30 ml of benzene. After the addition was complete, the reaction mixture was warmed to room temperature and stirred at room temperature for 3 hours. At the end of this period, the formed precipitate was filtered, and the benzene layer was separated. The aqueous layer was extracted twice with 50 ml of benzene. The combined benzene layer was dried over anhydrous sodium sulfate, and evaporated to dryness. The residue together with the precipitate obtained above was combined and recrystallized from ethanol to give 14.1 g (57 percent) of N-(4-chlorophenacyl) chloroacetamide.

(B) 2-Chloromethyl-5-(4-chlorophenyl)oxazole

A suspension of 12.3 g of N-(chlorophenacyl) chloroacetamide and 19.2 g of phosphorous oxychloride in 100 ml of benzene was heated at reflux for 2.5 hours. At the end of this period, the excess phosphorous oxychloride was removed in vacuo. The residue was poured into 200 ml of water and extracted with 100 ml of chloroform. The aqueous layer was extracted twice with 40 ml of chloroform.

The combined chloroform layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give 10.7 g (94%) of crude 2-chloromethyl-5-(4-chlorophenyl) oxazole. Recrystallization from aqueous ethanol gave pure 2-chloromethyl-5-(4-chlorophenyl) oxazole, M.P. 50°-60° C.

(C) 2-Ethylaminomethyl-5-(4-chlorophenyl) oxazole hydrochloride

To a solution of 2.3 g of 2-chloromethyl-5-(4-chlorophenyl) oxazole in 50 ml of ethanol was added 3.2 g of 70% ethylamine aqueous solution, and the resultant solution was allowed to stand at room temperature overnight. At the end of this time, the solvent and the excess ethylamine were distilled off under reduced pressure, and then 30 ml of water, 10 ml of 2N NaOH solution and 50 ml of chloroform were added. The chloroform layer was separated and the aqueous layer was extracted twice with 30 ml of chloroform. The combined chloroform layer was dried over anhydrous sodium sulfate, and the solvent was removed in vacuo to give 2.1 g of crude 2-ethylaminomethyl-5-(4-chlorophenyl) oxazole. This was dissolved in 15 ml of ethanol, and 5 ml of ethanolic saturated hydrogen chloride solution was added. Evaporation of the solvent followed by recrystallization from ethanol afforded 2.0 g (73 percent) of 2-ethylaminomethyl-5-(4-chlorophenyl) oxazole hydrochloride, M. P. 194°-6° C.

I.R. (KBr): 2,950, 2,740, 1,480, 1,450, 1,115 1,090 810 cm⁻¹. N.M.R. (CDCl₃, free base): δ 1.13 (triplet, -NCH₂ CH₃), 1.77 (singlet, --NH--), 2.72 (quartet, --NCH₂ CH₃), 3.90 (singlet --CH₂ N--), 7.15 ##STR34## 7.34 ##STR35## p.p.m. Analysis - Calcd. for C₁₂ H₁₃ N₂ O₁ Cl₁.HCl (percent): C, 52.76; H, 5.17; N, 10.26; Cl, 25.96. Found (percent): C, 52.73; H, 5.09; N, 10.25; Cl, 25.71.

Various other 2-aminomethyl-5-phenyloxazoles were synthesized in accordance with the procedure of Example 1, and the results are summarized in Table II.

                                      TABLE II                                     __________________________________________________________________________              ##STR36##                          Elemental analysis Upper:                                                     Calculated  (percent) Lower:                                                   Found(percent)                       No.                                                                               R.sub.1                                                                                  ##STR37##  Addition moiety                                                                       M. P. (° C)                                                                    Yield (%)                                                                           C    H    N    Cl                  __________________________________________________________________________         ##STR38##                                                                               NHCH.sub.3 HCl    186-188                                                                               79   58.80 58.72                                                                         5.83 5.90                                                                           12.47 12.26                                                                         15.78 15.69          2                                                                                  ##STR39##                                                                               NHCH.sub.2 CH.sub.3                                                                       HCl    166-168                                                                               76   60.37 60.19                                                                         6.33 11.74 11.68                                                                         14.85 14.75          3                                                                                  ##STR40##                                                                               NHCH.sub.2 CH.sub.2 CH.sub.3                                                              HCl    194-196                                                                               82   61.77 61.74                                                                         6.78 6.87                                                                           11.09 11.18                                                                         14.03 13.81          4                                                                                  ##STR41##                                                                                ##STR42## HCl    197-198                                                                               85   53.99 54.05                                                                         6.27 6.24                                                                           9.69 9.74                                                                           24.52 24.36          5                                                                                  ##STR43##                                                                               NH(CH.sub.2).sub.3 CH.sub.3                                                               HCl    150-152                                                                               75   63.03 63.08                                                                         7.17 7.23                                                                           10.50 10.49                                                                         13.29 13.21          6                                                                                  ##STR44##                                                                                ##STR45## HCl    179-181                                                                               88   60.37 60.30                                                                         6.33 6.41                                                                           11.74 11.56                                                                         14.85 14.83          7                                                                                  ##STR46##                                                                               NHCH.sub.3 2HCl   159-162                                                                               77   44.70 45.00                                                                         4.43 4.38                                                                           9.48 9.64                                                                           35.98 35.58          8                                                                                  ##STR47##                                                                                ##STR48## 2HCl   215-217                                                                               83   54.36 54.31                                                                         5.62 5.62                                                                           9.76 9.79                                                                           24.69 24.37          9                                                                                  ##STR49##                                                                                ##STR50## HCl    180-182                                                                               90   52.76 52.41                                                                         5.17 5.11                                                                           10.25 10.34                                                                         25.96 25.90          10                                                                                 ##STR51##                                                                               NHCH.sub.3 HCl    160-161                                                                               78   47.32 47.20                                                                         4.69 4.64                                                                           10.03 9.99                                                                          25.40 24.90          11                                                                                 ##STR52##                                                                               NHCH.sub.2 CH.sub.3                                                                       HCl    165-166                                                                               80   56.14 56.20                                                                         5.50 5.44                                                                           10.92 10.68               12                                                                                 ##STR53##                                                                               NHCH.sub.3 HCl    188-193                                                                               83   50.98 50.74                                                                         4.67 4.73                                                                           10.81 10.71                                                                         27.36 27.16          13                                                                                 ##STR54##                                                                               NHCH.sub.3 HCl    201-203                                                                               85   50.98 50.80                                                                         4.67 4.60                                                                           10.81                                                                               27.36 27.20          14                                                                                 ##STR55##                                                                               NHC.sub.2 H.sub.5 193-196                                                                               78   52.76 52.96                                                                         5.17 5.07                                                                           10.26 10.20                                                                         25.96 25.90           15                                                                                ##STR56##                                                                               NHC.sub.2 H.sub.5                                                                         HCl    206-209                                                                               75   45.38 45.20                                                                         4.44 4.40                                                                           8.82  8.80                16                                                                                 ##STR57##                                                                               NHC.sub.2 H.sub.5                                                                         HCl    195-199                                                                               85   46.86 46.88                                                                         4.26 4.26                                                                           9.11 9.05                                                                           34.58 34.44          17                                                                                 ##STR58##                                                                               NHCH.sub.2 CH.sub.2 CH.sub.3                                                              HCl    235-240                                                                               84   54.37 54.11                                                                         5.62 5.45                                                                           9.75 9.53                                                                           24.69 24.58          18                                                                                 ##STR59##                                                                               NHCH.sub.2 CH.sub.2 CH.sub.3                                                              HCl    199-201                                                                               78   54.37 54.20                                                                         5.62 5.50                                                                           9.75 9.70                                                                           24.69 24.60          19                                                                                 ##STR60##                                                                               NHCH.sub.2 CH.sub.2 CH.sub.3                                                              HCl    183-185                                                                               80   57.67 57.60                                                                         5.96 5.94                                                                           10.35 10.18               20                                                                                 ##STR61##                                                                                ##STR62## HCl . 1/2 H.sub.2 O                                                                   124-126                                                                               75   54.20 54.47                                                                         6.17 6.05                                                                           9.03 8.98                                                                           22.85 23.03          21                                                                                 ##STR63##                                                                               NHCH.sub.2 CH.sub.3                                                                       HCl    219-221                                                                               70   52.76 52.96                                                                         5.17 10.26 10.20               __________________________________________________________________________     Compound                                                                        ##STR64##                                  Elemental analysis Upper:                                                     Calculated (%) Lower: Found(%)                                                 1                                                                 M. P.  Yield                                     No. R.sub.1       Addition moiety                                                                            (° C)                                                                          (%)   C    H    N    Cl                   __________________________________________________________________________     21                                                                                  ##STR65##    2HCl        190-195                                                                               69    53.34 53.28                                                                         6.43 6.36                                                                           11.66 11.65                                                                         19.68 19.63          22                                                                                  ##STR66##    2HCl        196-202                                                                               71    50.80 50.58                                                                         5.86 5.87                                                                           11.11 11.06                                                                         18.74 18.82          23                                                                                  ##STR67##    2HCl        195-198                                                                               73    48.68 48.59                                                                         5.62 5.55                                                                           10.65 10.65               24                                                                                  ##STR68##    2HCl        185-190                                                                               68    48.68  48.38                                                                        5.62 5.60                                                                           10.65 10.62                                                                         26.95 26.73          25                                                                                  ##STR69##    2HCl        195-200                                                                               72    43.76 43.94                                                                         5.05 4.93                                                                           9.57 9.61                 26                                                                                  ##STR70##    2HCl        218-223                                                                               74    44.78 44.68                                                                         4.93 5.01                                                                           9.79 9.61                                                                           33.04 32.93          __________________________________________________________________________

The following compounds are prepared in a similar manner.

2-butylaminomethyl-5-(4-chlorophenyl) oxazole

2-sec-butylaminomethyl-5-(4-chlorophenyl) oxazole

2-isobutylaminomethyl-5-(4-chlorophenyl) oxazole

2-octylaminomethyl-5-(4-chlorophenyl) oxazole

2-ethylaminomethyl-5-(3-chlorophenyl) oxazole

2-propylaminomethyl-5-(2-chlorophenyl) oxazole

2-methylaminomethyl-5-(4-bromophenyl) oxazole

2-methylaminomethyl-5-(3-bromophenyl) oxazole

2-methylaminomethyl-5-(2-bromophenyl) oxazole

2-ethylaminomethyl-5-(3-bromophenyl) oxazole

2-ethylaminomethyl-5-(2-bromophenyl) oxazole

2-propylaminomethyl-5-(4-bromophenyl) oxazole

2-propylaminomethyl-5-(3-bromophenyl) oxazole

2-propylaminomethyl-5-(2-bromophenyl) oxazole

2-methylaminomethyl-5-(4-fluorophenyl) oxazole

2-methylaminomethyl-5-(3-fluorophenyl) oxazole

2-methylaminomethyl-5-(2-fluorophenyl) oxazole

2-ethylaminomethyl-5-(4-fluorophenyl) oxazole

2-ethylaminomethyl-5-(3-fluorophenyl) oxazole

2-ethylaminomethyl-5-(2-fluorophenyl) oxazole

2-propylaminomethyl-5-(3-fluorophenyl) oxazole

2-propylaminomethyl-5-(2-fluorophenyl) oxazole 2-diethylaminomethyl-5-(4-chlorophenyl) oxazole

2-[4-(2-hydroxyethyl)piperazinylmethyl]-5-(2-fluorophenyl) oxazole

2-[4-(2-hydroxyethyl)piperazinylmethyl]-5-(3-fluorophenyl) oxazole

2-[4-(2-hydroxyethyl)piperazinylmethyl]-5-(2-bromophenyl) oxazole

2-[4-(2-hydroxyethyl)piperazinylmethyl]-5-(3-bromophenyl) oxazole

2-[4-(2-hydroxyethyl)piperazinylmethyl]-5-(4-iodophenyl) oxazole

EXAMPLE 2 (A) N-[5-(4-chlorophenyl)-2-oxazolyl]methylphthalimide

A suspension of 2.3 g of 2-chloromethyl-5-(4-chlorophenyl) oxazole and 1.94 g of potassium phthalimide in 15 ml of dimethylformamide was stirred at room temperature for one hour. The reaction mixture was poured into 300 ml of water, and the resultant precipitate was filtered and recrystallized from ethanol to give 2.4 g (71 percent) of N-[5-(4-chlorophenyl)-2-oxazolyl]methylphthalimide.

(B) 2-aminomethyl-5-(4-chlorophenyl) oxazole hydrochloride

A solution of 3.4 g of N-[5-(4-chlorophenyl)-2-oxazolyl]methylphthalimide and 0.55 g of 100% hydrazine hydrate in 50 ml of ethanol was heated at reflux for one hour. At the end of this period, the formed precipitate was filtered off, and the filtrate was evaporated to dryness in vacuo. The residue was shaken with 2N HCl - chloroform and the 2N HCl - layer was evaporated to dryness under vacuo. The residue was recrystallized from ethanol to give 1.9 g (78 percent) of 2-aminomethyl-5-(4-chlorophenyl) oxazole hydrochloride, M.P. 200° C (decomposition).

I.R. (KBr, free base): 3,340 1,550 1,480 1,100 940 820 cm⁻¹. N.M.R. (CDCl₃, free base): δ 4.50 ##STR71## 7.70 ##STR72## 7.73 (double doublet, ##STR73##

Analysis - Calcd. for C₁₀ H₁₀ ON₂.HCl (percent): C, 49.00; H, 4.11; N, 11.43; Cl, 28.93. Found (percent): C, 48.79; H, 4.20; N, 11.18; Cl, 29.06.

Various other 2-aminomethyl-5-phenyloxazoles were synthesized in accordance with the procedure of Example 2, and the results are summarized in Table III.

                                      TABLE III                                    __________________________________________________________________________     Compound                                                                        ##STR74##           M.P.                                                                                Yield                                                                              Elemental Analysis Upper: Calculated                                          (percent) Lower: Found(percent)                   No.                                                                               R.sub.1  Addition moiety                                                                        (° C)                                                                        (%) C  H   N  Cl                                      __________________________________________________________________________         ##STR75##                                                                              HCl     232-236                                                                             81  57.01 56.69                                                                       5.26 5.26                                                                          13.30 13.28                                                                       16.83 17.18                             2                                                                                  ##STR76##                                                                              HCl     233-237                                                                             78  52.52 52.38                                                                       4.41 4.41                                                                          12.25 12.05                                3                                                                                  ##STR77##                                                                              HCl     194-199                                                                             79  49.00 49.10                                                                       4.11 4.11                                                                          11.43 11.40                                                                       28.93 28.83                             __________________________________________________________________________

The following compounds are prepared in a similar manner.

2-aminomethyl-5-(3-chlorophenyl) oxazole

2-aminomethyl-5-(4-bromophenyl) oxazole

2-aminomethyl-5-(3-bromophenyl) oxazole

2-aminomethyl-5-(2-bromophenyl) oxazole

2-aminomethyl-5-(4-fluorophenyl) oxazole

2-aminomethyl-5-(3-fluorophenyl) oxazole

2-aminomethyl-5-(2-fluorophenyl) oxazole

EXAMPLE 3 Tablets suitable for oral administration

Tablets containing the ingredients indicated below may be prepared by conventional techniques.

    ______________________________________                                                              Amount per                                                Ingredient           tablet (mg)                                               ______________________________________                                         5-(4-chlorophenyl)-2-                                                          ethylaminomethyloxazole                                                        hydrochloride        125                                                       Lactose              30                                                        Corn starch          20                                                        Crystalline cellulose                                                                               75                                                        Silica               2                                                         Magnesium stearate   2                                                         Total                254       mg                                              ______________________________________                                    

EXAMPLE 4 Capsules for oral administration

Capsules of the below were made up by thoroughly mixing together batches of the ingredients and filling hard gelatin capsules with the mixture.

    ______________________________________                                                              Amount per                                                Ingredient           capsule (mg)                                              ______________________________________                                         5-(4-chlorophenyl)-2-                                                          ethylaminomethyloxazole                                                        hydrochloride        250                                                       Magnesium stearate   2                                                         Lactose              48                                                        Total                300       mg                                              ______________________________________                                    

EXAMPLE 5 Sterile solution for infusion

A 0.25 g portion of 5-(4-chlorophenyl)-2-ethylaminomethyloxazole hydrochloride is dissolved in saline to give a total volume of 500 ml and the resulting solution is then sterilized. 

What is claimed as new and intended to be covered by Letters Patent is:
 1. A 2-aminomethyl-5-phenyloxazole having the formula (I): ##STR78## wherein R₁ is phenyl or halophenyl; R' is 4-(2-hydroxyethyl)-1-piperazinyl or the pharmaceutically acceptable acid addition salts thereof.
 2. The compound of claim 1, wherein R₁ is selected from the group consisting of phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl and 4-iodophenyl; R' is 4-(2-hydroxyethyl)-1-piperazinyl.
 3. The compound of claim 2, wherein R₁ is selected from the group consisting of phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-fluorophenyl and 4-bromophenyl; and R' is 4-(2-hydroxyethyl)-1-piperazinyl.
 4. A method of meliorating inflammation in warm blooded animals, which comprises administering to said animal an anti-inflammatory effective amount of a compound having the formula (I): ##STR79## wherein R₁ is phenyl or halophenyl; R' is 4-(2-hydroxyethyl)-1-piperazinyl.
 5. A compound of claim 3, which is 2-[4-(2-hydroxyethyl)-1-piperazinylmethyl]-5-(4-chlorophenyl) oxazole. 